Novel use of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and its physiologically acceptable salts

ABSTRACT

(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or a physiologically acceptable salt thereof and/or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or a physiologically acceptable salt thereof are used for the manufacture of a medicament for the treatment of extrapyramidal movement disorders and/or adverse effects in extrapyramidal movement disorders.

[0001] The present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders and/orfor the manufacture of a medicament for the treatment of adverse effectsof anti-Parkinsonian drugs in extrapyramidal movement disorders and/orfor the manufacture of a medicament for the treatment of extrapyramidalsymptoms (EPS) induced by neuroleptics.

[0002] 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane,(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts thereof (U.S. Pat. No. 5,767,132,column 9, lines 6 to 32) and a process (U.S. Pat. No. 5,767,132,Examples 1, 5 and 19) by which it/they can be prepared are known fromU.S. Pat. No. 5,767,132. The compounds which are referred to herein aredescribed in the patent as a combined selective dopamine D₂ receptorantagonist and 5-HT_(1A) receptor agonist. Therefore, the use of2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane and itsphysiologically acceptable acid addition salts and the use of itsenantiomer(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane andits physiologically acceptable acid addition salts for the manufactureof a medicament for prophylaxis and control of the sequelae of cerebralinfarction (apoplexia cerebri) such as stroke and cerebral ischaemia,for prophylaxis and control of cerebral disorders, e.g. migraine,especially in geriatrics in a manner similar to certain ergot alkaloids,the treatment of anxiety, tension and depression states, sexualdysfunctions caused by the central nervours system, for disturbances insleep or absorption of food or for the treatment of psychosis(schizophrenia) is disclosed.

[0003] Additionally, they are suitable to eliminate cognitivedeficiencies, to improve powers of learning and memory and to treatAlzheimer's disease. They can be furthermore used for treatingside-effects in the treatment of hypertension, in endocrinology andgynecology, e.g. for the treatment of acromegaly, hypogonadism,secondary amenorrhea, premenstrual syndrome or undesired puerperallactation.

[0004] The invention had the object of providing novel uses for(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane,(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane andtheir physiologically acceptable salts.

[0005] It has been found that(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts also have therapeutic activity againstextrapyramidal movement disorders such as idiopathic Parkinsons'sdisease, Parkinson syndromes, dyskinetic, choreatic, or dystonicsyndromes, tremor, Gilles de la Torette syndrome, ballism, myoclonus,restless legs syndrome or Wilsons's disease, as well as extrapyramidalmotoric disturbances [synonymous extrapyramidal symptoms (EPS)] inducedby neuroleptics.

[0006] Additionally it has been found that(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts have therapeutic activity againstadverse effects of anti-Parkinsonian drugs in extramyramidal movementdisorders, in particular against dopaminomimetic adverse effects ofanti-Parkinsonian drugs in idiopathic Parkinson's disease or Parkinsonsyndromes. Furthermore it has been found that(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts show an extremely low liability toinduce extrapyramidal side effects. Extrapyramidal motor side effects ine.g. rodents are measured by the ability of a drug to induce catalepsy.Catalepsy is defined as a state where an animal continues to remain inan unnormal (nonphysiological ‘uncomfortable’) posture for a long time(e.g.: M. E. Stanley and S. D. Glick, Neuropharmacology, 1996; 15:393-394; C. J. E. Niemegeers and P. Janssen, Life Sci., 1979, 201-2216).For example, if a hindpaw of a rat is placed on an elevated level, e.g.a platform elevated 3 cm above ground level, a normal rat immediatelywithdraws the hindpaw from the platform to the ground level. Acataleptic rat remains in this unnatural posture even for minutes.

[0007] Although(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts have a dopamine antagonistic mechanismof action which is known to induce extrapyramidal motor side effects (C.J. E. Niemegeers and P. Janssen, Life Sci., 1979, 201-2216), unexpectely(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts do not induce any catalepsy in rats indoses up to 500 fold higher compared to the doses effective in theanimal models indicative for the before-mentioned therapeuticindications.

[0008] Even more unexpectedly,(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts moreover are able to prevent catalepsyinduced by conventional antidopaminergic drugs and even reverses alreadyexisting catalepsy induced by conventional antidopaminergic drugs suchas haloperidol; the doses for this anticataleptic effect are in the samedose-range shown to be effective in the animal models indicative for thebefore-mentioned therapeutic indications.

[0009] Beneficial effects on the extrapyramidal motoric system havepreviously been described for other drugs with 5-HT_(1A) agonisticaction. Buspirone for example, which is an anxiolytic drug by nature,exhibits moderate anti-dyskinetic properties in advanced Parkinsonpatients (B. Kleedorfer et al., J Neurol Neurosurg Psychiatry, 1991, 54:376-377; V. Bonifati et al., Clin Neuropharmacol, 1994, 17: 73-82). Themain mechanism of action is obviously via stimulation of 5-HT_(1A)receptors of the raphe nigral and raphe striatal pathways. In contrastto buspirone,(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts thereof are more potent agonists at the5-HT_(1A) receptor (IC₅₀ of buspirone: 30 nmol/l).

[0010] Furthermore,(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts thereof exhibit a D₂ antagonism underincreased doses which represents an additional advantage in comparisonto conventional 5-HT_(1A) agonists like buspirone. On one hand, the D₂antagonism lowers the risk of psychotic reactions caused by thestimulation of serotonin receptors and, on the other hand, emphasisesindirectly the D₁ properties of the co-administered non-selective D₁/D₂agonist l-dopa. A more selective stimulation of D₁ receptors is known tobe beneficial for the treatment of dyskinesias in Parkinson's disease(P. J. Blanchet et al., J Neural Transm, 1995, 45 (Suppl.): 103-112).Therefore both, the 5-HT_(1A) agonistic and the D₂ antagonisticproperties of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts thereof, contribute to the advantageouseffects on the extrapyramidal motoric system.

[0011] The pharmacological profile of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridyl-methyl-aminomethyl]-chromaneor physiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts is furthermore characterized by a highaffinity to the dopamine D₃ receptor. The D₃ receptor is obviouslyinvolved in the pathogenesis of dyskinesia. So an association between agenetic polymorphism of the dopamine D₃ receptor and the disposition todevelop tardive dyskinesia has recently been reported (Segmann et al.1999, Mol-Psychiatry 4: 247). Additionally, there is obviously anincreased density of dopamine D₃ receptors in Parkinson patients withl-dopa-induced dyskinesia. Therefore, the interaction of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts with the dopamine D₃ receptor is anadditional important mechanism leading to beneficial effects on theextrapyramidal system, in particular in the treatment of dyskinesia.

[0012] The atypical neuroleptic clozapine is regarding theextrapyramidal effects—but not regarding structure or sideeffects—congruent with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts particularly in scope of theanticataleptic properties. Recent studies provide evidence thatclozapine ameliorates dyskinesias in Parkinson's disease (F. Perelli etal., Acta Neurol Scan, 1998, 97: 295-299; P. Pollak et al., Lancet,1999, 353: 2041-2041). Besides that, clozapine is known to have avariety of other beneficial effects on extrapyramidal movementdisorders, like in tardive dyskinesia, tremor, Huntington's disease,Tourette's syndrome, akathisia and dopaminomimetic psychosis (C.Pfeiffer and M. L. Wagner, Am J Hosp Pharm, 1994, 51: 3047-3053).(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts thereof improve these kinds of movementdisorders even without bearing the risk of the fatal side effects ofclozapine like agranulocytosis and acute nephritis (J. Alvir et al., NEngl J Med, 1993, 329: 162-167; T. J. Elias et al., Lancet, 1999, 354:1180-1181).

[0013] Therefore, the present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orphysiologically acceptable salts thereof and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane orphysiologically acceptable salts thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders.

[0014] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0015] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(−)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0016] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of extrapyramidal movement disordersin which the pharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0017] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of extrapyramidal movement disordersin which the pharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0018] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of their biocompatible salts together with at least one solid,liquid or semiliquid excipient or adjunct for the treatment ofextrapyramidal movement disorders.

[0019](R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromaneand/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ortheir physiologically acceptable salts, useful for the treatment ofextrapyramidal movement disorders, in particular for the treatment ofidiopathic Parkinson's disease, Parkinson syndromes, dyskinetic,choreatic or dystonic syndromes, extrapyramidal motoric adverse effectsof neuroleptics, tremor, Gilles de la Tourette syndrome, ballism,myoclonus, restless legs syndrome or Wilson's disease and/or useful forthe treatment of adverse effects in idiopathic Parkinson's disease orParkinson syndromes including medicinal compositions as defined below,are preferably administered in doses from 0.1 to 100 mg, preferentiallybetween approximately 1 and 20 mg. The composition may be administeredonce or more times a day, e.g. 2, 3, or 4 times daily. The specific dosefor each patient depends on all sorts of factors, e.g. on the activityof the specific compound employed, on the age, body weight, generalstate of health, on sex, diet, time and route of administration, on theexcretion rate, pharmaceutical substance combination and on the severityof the particular disorder to which the therapy relates. Oraladministration is preferred, but also parenteral routes ofadministration (e.g. intravenous or transdermal) can be utilized.

[0020] Anti-Parkinsonian drugs are conventional drugs such as l-dopa(levodopa) and l-dopa combined with benserazide or carbidopa, dopamineagonists such as bromocriptine, apomorphine, cabergoline, pramipexol,ropinirol, pergolide, dihydro-α-ergocriptine or lisuride plus all drugsacting via stimulation of dopamine receptors, inhibitors ofcatechol-O-methyl transferase (COMT) such as entacapone or tolcapone,inhibitors of monoamine oxidase (MAO) such as selegiline and antagonistsof N-methyl-D-aspartate (NMDA) receptors such as amantadine or budipine.

[0021] Adverse effects of said anti-Parkinsonian drugs are all types ofdyskinesias, such as choreic, dystonic, ballistic and myoclonicdyskinesia, as well as motor (response) fluctuations or psychoticstates.

[0022] Therefore, the present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in idiopathic Parkinson's disease.

[0023] Treatment of adverse effects of conventional anti-Parkinsoniandrugs as defined above are determined in a modification of the animalmodel of the Parkinsonian cynomolgus monkey according to P. J. Blanchetet al., Exp. Neurology 1998; 153: 214-222. Monkeys render parkinsonianby repeated injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP). The Parkinsonian monkeys are chronically treated with thestandard l-dopa therapy according to P. J. Blanchet et al., Mov.Disord., 1998; 13: 798-802. Longterm treatment with l-dopa inducesextrapyramidal motor side effects and psychotic states which are bothqualitatively and quantitatively, assessed by the Abnormal InvoluntaryMovement Scale (P. J. Blanchet et al., Mov. Disord. 1998; 13: 798-802)for different body parts (face, neck, trunk, each limb) and by ratingfor psychotic states by observing the monkey's attention, reactivity andmobility.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromaneand/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanereduced overall choreiform dyskinesias and dystonic dyskinesias as wellas psychotic states.

[0024] A typical study to investigate the efficacy of the compoundsaccording to the invention for adverse effects in Parkinson's disease isdescribed in the following. 40 patients of either sex with advancedidiopathic Parkinson's disease complicated by “peak-dose” dyskinesiaparticipate in a double-blind, cross-over study. The main inclusioncriteria are Hoehn & Yahr stage ≧2.5 (lit.: Hoehn H. M. et al, Neurology1967; 17: 427-442), aged 40-75 years, symptom duration of at least 5years, and a l-dopa treatment duration of at least 3 years.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride or placebo is administered as “add on” to the conventionalParkinson treatment, which is maintained unchanged during the wholestudy. The dose of blinded medication is titrated over a period of 3weeks in a range from 2.5 to 10 mg b.i.d. Then the medication is keptconstant for 1 week. Before the start of titration and at the end of thetreatment period a l-dopa challenge is performed according to P. Damieret al. (Movement Disord, 1999, 14 (Suppl. 1), 54-59) using videorecording. The main outcome measure of the protocol is the mean scorefor dyskinesia during the first hour in the “on” state after l-dopachallenge. Therefore, the investigator assesses every minute theseverity of dyskinesia (0=absent, 4=severe disabling involuntarymovements) from 0 to 4 in seven parts of the body (upper and lowerlimbs, face, trunk, neck). After a 2-week wash-out period the two studyarms are crossed over and the protocol is repeated. The statisticalanalysis of the mean dyskinesia scores demonstrates a significantclinical improvement under treatment with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride.

[0025] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0026] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0027] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of adverse effects ofanti-Parkinsonian drugs in idiopathic Parkinson's disease in which thepharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0028] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts together with at least one solid, liquidor semiliquid excipient or adjunct for the treatment of adverse effectsof anti-Parkinsonian drugs in idiopathic Parkinson's disease.

[0029] Furthermore, the present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts, for the manufacture of a medicament forthe treatment of idiopathic Parkinson's disease.

[0030] A typical animal model for idiopathic Parkinson's disease is theParkinsonian cynomolgus monkey according to P. J. Blanchet et al., Exp.Neurology 1998; 153: 214-222. Monkeys render parkinsonian by repeatedinjections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).Parkinsonian symptoms are qualitatively assessed by the use of the LavalUniversity Disability Scale (B. Gomez-Mancilla et al., 1993; Mov.Disord. 8: 144-150) measuring the following symptoms: posture, mobility,climbing, gait, holding food, vocalizing, grooming, social interaction.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanereduced all the parkinsonian symptoms and increased total activity.

[0031] A typical study to investigate the efficacy of the compoundsaccording to the invention in the treatment of idiopathic Parkinson'sdisease is described in the following. 180 patients of either sex withidiopathic Parkinson's disease participate in a double-blind study. Themain inclusion criteria are Hoehn & Yahr stage ≧2.0 (Hoehn H. M. et al,Neurology 1967; 17: 427-442), aged 50-80 years, symptom duration of atleast 5 years.(R/S)-(±)-2-[5-(4-fluoro-phenyl)-3-pyridyl-methyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orplacebo is administered as “add on” to the conventional Parkinsontreatment, which is maintained unchanged during the whole study. Thedose of blinded medication is titrated over a period of 4 weeks in arange from 2.5 to 10 mg b.i.d. Then the medication is kept constant for1 week. Before the start of titration, at the end of the treatmentperiod and 2 weeks after the end of the tiration period an assessment isperformed in each patients using the unified Parkinson's disease ratingscale (UPDRS part I to V according to S. Fahn et al., in: Recentdevelopments in Parkinson's disease, vol. 2, MacMillan healthinformation 1987, 153-163). This allows to detect simultaneously abeneficial effect of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts, in particular of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(/+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride, on the global motoric function, on dystonia, motorfluctuations, and on psychosis. Furthermore, the efficacy to treattremor is shown by the means of the UPDRS. The statistical analysis ofthe UPDRS scores demonstrates a significant clinical improvement undertreatment with(R/S)-(±)-2-[5-(4-fluoro-phenyl)-3-pyridyl-methyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0032] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of idiopathic Parkinson's disease inwhich the physiologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0033] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts together with at least one solid, liquidor semiliquid excipient or adjunct for the treatment of idiopathicParkinson's disease.

[0034] The limiting factor of Parkinson treatment with l-dopa and/ordopamine agonists is often the occurence of psychosis or dyskinesia andother motor fluctuations.

[0035] It has been found that(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof enhance the anti-Parkinsonianeffect of anti-Parkinsonian drugs as defined above without inducingextrapyramidal side effects.

[0036] Therefore, the add-on therapy with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof and/or the therapy with(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof, in particular of theirhydrochlorides, now opens the possibility to increase the doses ofl-dopa and/or dopamine agonists and/or all other anti-Parkinsonian drugsas defined above in order to counteract periods of insufficient motility(“off” phases) without provoking the above mentioned side effects. Thatrepresents an entirely novel approach in the treatment of Parkinson'sdisease leading to a significant benefit for the patients.

[0037] Thus, the invention relates to a pharmaceutical compositioncomprising, as active principles, (i)(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-pyridylmethyl-aminomethyl]-chromaneor a physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof, and (ii) at least oneanti-Parkinsonian drug, in combination with one or more pharmaceuticallyacceptable excipients.

[0038] Particularly, the invention relates to a pharmaceuticalcomposition comprising, as active principles, (i)(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride, and (ii) l-dopa or l-dopa combined with benserazide orcarbidopa, in combination with one or more pharmaceutically acceptableexcipients.

[0039] The ratios of the respective amounts of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane oron of its physiologically acceptable salts and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its physiologically acceptable salts and of the conventionalanti-Parkinsonian drug thus vary in consequences. Preferably, the weightratio of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its biocompatible salts or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its physiologically acceptable salts to the conventionalanti-Parkinsonian drug ranges from 1:1 to 1:100, preferably from 1:10 to1:90 and better still from 1:40 to 1:60.

[0040] Another subject of the present invention is additionally the useof (R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromaneor one of its physiologically acceptable salts or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its physiologically acceptable salts in combination with at leastone anti-Parkinsonian drug, for the preparation of a medicinalcombination intended to enhance the anti-Parkinsonian effect of saidanti-Parkinsonian drugs.

[0041] According to the invention, the term “medicinal combination” isinteded to refer either to a pharmaceutical composition as definedabove, in which the two active principles or compounds are the essentialconstituents of the same composition, or to a kit comprising twoseparate compositions, the first comprising(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its physiologically acceptable salts as sole active principle,and the second comprising at least one anti-Parkinsonian drug as activecompound.

[0042] According to the invention, the term “medicinal combination” isinteded to refer either to a pharmaceutical composition as definedabove, in which the two active principles or compounds are the essentialconstituents of the same composition, or to a kit comprising twoseparate compositions, the first comprising(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane orone of its physiologically acceptable salts as sole active principle,and the second comprising at least one anti-Parkinsonian drug as activecompound.

[0043] When the medicinal combination is in the form of a kit, theadministration of the two compositions constituting this kit, althoughcarried out separately, is simultaneous for a combined therapy. It ispreferred to use(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane inthe form of the hydrochloride.

[0044] Adverse effects of anti-Parkinsonian drugs as defined above areadditionally known in particular in Parkinson syndromes.

[0045] Parkinson syndromes are e.g. multiple system atrophies (MSA),Steele-Richardson-Olszewski syndrome (=progressive supranuclear palsy),cortico-basal degeneration, olivo-ponto cerebellar atrophy or Shy Dragersyndrome.

[0046](R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof are useful for the treatment ofParkinson syndromes in particular of multiple system atrophies.

[0047] Therefore the present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of adverse effects in Parkinson syndromes.

[0048] The present invention relates additionally to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of Parkinson syndromes.

[0049] A typical animal model is the reserpinized rat or mouse (e.g. M.S. Starr and B. S. Starr, J. Neural Transm.—Park. Dis. Dement. Sect.,1994; 7: 133-142; M. Gossel et al., J. Neural Transm.—Park. Dis. Dement.Sect., 1995; 10: 27-39; N. R. Hughes et al., Mov. Disord., 1998; 13:228-233). Reserpine is a potent depleter of monoamines and producesnearly complete akinesia in both species. Prominent 24 h afterapplication, the distance travelled and the time active is nearly zeroas measured in conventional activity meters.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof dose-dependently reducedakinesia, i.e. restored distance travelled and time active to about thelevel of normal animals.

[0050] Another more recent animal model is the striatonigraldegeneration approach in the rat according to G. K. Wenning et al., J.Neural Transm. Suppl., 1999; 55: 103-113. Rats receive an unilateralinjection of 6-hydroxydopamine into the left medial forebrain bundlefollowed by an injection of quinolinic acid into the ipsilateralstriatum inducing nigrostriatal degeneration. The degeneration resultsin turning behavior to a challenge with dopaminomimetics such asapomorphine or amphetamine. Turning behavior is measured by an automatedrecorder. Turning behavior induced by apomorphine or amphetamine isdose-dependently antagonized by(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof.

[0051] Multiple system atrophy (MSA) is due to an expansiveneurodegeneration in the extrapyramidal and autonomic nervous systemwhich leads to an akinetic Parkinsonian syndrome with vegetativedisturbances. In contrast to idiopathic Parkinson's disease the densityof central dopamine receptors is markedly decreased and therefore, MSApatients poorly respond to dopaminergic drugs. Since(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-(5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof act predominantly via serotoninreceptors on the extrapyramidal system, they are able to improve themotor performance in these otherwise mostly untreatable patients.

[0052] A typical study to investigate the efficacy of the compoundsaccording to the invention in MSA patients encompasses 30 patients ofeither sex with a symptom duration of at least 5 years and a significantreduction of central dopamine receptors in positron emission tomography(PET) scan. The study design is similar to that described above forParkinson's disease.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride or placebo is titrated as “add on” to the conventionaltreatment (dose range 2.5 to 20 mg b.i.d.). Before the start oftitration and at the end of the treatment period a complete UPDRSassessment is performed in each patient (primary outcome measure). Aftera 2-week wash-out period the two study arms are crossed over and theprotocol is repeated. Statistical analysis of UPDRS demonstrates asignificant clinical improvement under treatment with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride.

[0053] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of adverse effects ofanti-Parkinsonian drugs in Parkinson syndromes in which thepharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0054] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of adverse effects ofanti-Parkinsonian drugs in Parkinson syndromes in which thepharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0055] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofadverse effects of anti-Parkinsonian drugs in Parkinson syndromes.

[0056] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of Parkinson syndromes in which thepharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0057] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of Parkinson syndromes in which thepharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0058] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofParkinson syndromes.

[0059] The present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof and/or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dyskinetic and/or choreatic syndromes.

[0060] Dyskinetic and/or choreatic syndromes are e.g. Huntington'sdisease, minor chorea or chorea of pregnancy.

[0061](R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof are in particular useful for thetreatment of Huntington's disease.

[0062] A typical animal model is the systemic 3-nitropropionic acid(3-NP) model in rats according to C. V. Borlongan et al., Brain Res.,1995; 697: 254-257. Rats are treated with injections of the selectivestriatal neurotoxin 3-NP i.p. every fourth day (C. V. Borlongan et al.,Brain Res. Protocols, 1997; 1: 253-257). After two injections of 3-NP,rats display nocturnal hyperactivity reflecting symptoms of earlyHuntington's disease, whereas rats treated with four injections of 3-NPdisplay nocturnal akinesia (hypoactivity) reflecting symptoms of lateHuntington's disease. Nocturnal activity is automatically measured inconventional acitivity cages by infrared beams.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof reduce both the nocturnalhyperactivity and akinesia.

[0063] A typical trial to establish the effect of the compoundsaccording to the invention on chorea, voluntary motor performance, andfunctional disability in patients with Huntington's disease encompasses32 genetically diagnosed patients.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-chromane hydrochlorideor (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride or placebo is administered as “add on” to the conventionaltreatment, which is maintained unchanged during the whole study. Thedose of blinded medication is titrated over a period of 3 weeks in arange from 2.5 to 20 mg b.i.d. Then the medication is held constant for1 week. Assessments are performed in the week before and at the last dayof the trial. Chorea is scored using the abnormal involuntary movementscale (AIMS, W. Guy, in: ECDEU assessment manual. Rockville Md.: USdept. of health, education and welfare, 1976: 534-537), the unifiedHuntington's disease rating scale (UHDRS, Huntington study group, 1996,Movement Disord, 11: 136-42), and judgement of video recordings.Voluntary motor performance is assessed using the UHDRS motor scale.Patients and their partners complete a questionnaire regardingfunctional disability. Statistical analysis demonstrates significantimprovement of voluntary and involuntary motor performance in Huntingtonpatients under treatment with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof.

[0064] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0065] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of dyskinetic and/or choreaticsyndromes, in particular for the treatment of Huntington's disease, inwhich the pharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0066] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0067] Therefore, the invention relates to the use for the manufactureof a medicament for the treatment of dyskinetic and/or choreaticsyndromes, in particular for the treatment of Huntington's disease, inwhich the pharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0068] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofdyskinetic and/or choreatic syndromes.

[0069] The present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dystonic syndromes.

[0070] Dystonic syndromes are e.g. spasmalic torticollis, writer'scramp, blepharospasm, Meige syndrome or dopasensitive dystonia.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof is in particular useful for thetreatment of spasmalic torticollis and/or blepharospasm.

[0071] A typical animal model is the mutant dystonic hamster accordingto A. Richter and W. Löscher, Prog. Neurobiol. 1998; 54: 633-677. Inthis genetically dystonic hamsters, dystonic attacks are provoked bytaking the animal from the home cage and placing it on a balance. Thedystonic syndrome consists of a sequence of abnormal movements, and theseverity of the single symptoms is rated by a scoring system.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof dose-dependently reduce theseverity of dystonic symptoms.

[0072] To demonstrate the efficacy of the compounds according to theinvention in dystonic syndromes, a double-blind, placebo-controlledstudy is performed in patients with cervical dystonia (spasmodictorticollis) who do not tolerate injection of botulinum toxin.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride is titrated as described above in the range from 2.5 mg to20 mg b.i.d. The Toronto western spasmodic torticollis rating scale(TWSTRS, C. L. Comella et al., 1997, Movement Disord, 12: 570-575) isused as primary outcome measure. A significant improvement in the TWSTRSscores is noted for the patients treated with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof.

[0073] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0074] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of dystonic syndromes, in particular ofspasmalic torticollis and/or blepharospasm, in which thepharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0075] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0076] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of dystonic syndromes, in particular ofspasmalic torticollis and/or blepharospasm, in which thepharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0077] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofdystonic syndromes.

[0078] The present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal symptoms induced byneuroleptics.

[0079] Extrapyramidal motoric disturbances induced by neuroleptics aree.g. early dyskinesia, dystonia, akathisia, parkinsonoid, in particularbradykinesia, or tardive dyskinesia.

[0080](R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof are useful particularly for thetreatment of akathisia and/or tardive dyskinesia and/or parkinsonoid.

[0081] A typical animal model is neuroleptics-induced muscle rigidity inrats according to S. Wolfarth et al, Arch. Pharmacol. 1992; 345:209-212. Rats are challenged with the conventional neuroleptic drughaloperidol which enhances muscle tone. Muscle tone iselectromechanically measured as the resistence to passive flexion andextension of the hind limb.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof thereof decrease the mucle toneenhanced by haloperidol.

[0082] Another typical animal model is the neuroleptics sensitizedmonkey according to D. E. Casey, Psychopharmacology, 1996; 124: 134-140.Monkeys treated repeatedly with conventional neuroleptics are highlysensitive to a subsequent challenge dose of neuroleptic drugs. Whenchallenged, the monkeys immediately show extrapyramidal motor sideeffects such as dystonia, dyskinesias, akathisia, and bradykinesia whichare rated by a scoring system. The conventional neuroleptic drughaloperidol is given as a challenge. When the before-mentionedextrapyramidal motor side effects occur,(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof is administered;(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanedose-dependently reduce the extrapyramidal motor side effects.

[0083] Tardive dyskinesia is a common adverse effect of long-termtreatment with neuroleptics. A typical study to investigate the efficacyof the compounds according to the invention in tardive dyskinesia isdescribed in the following. 32 schizophrenic (DSM-III-R) inpatients aged25-60 years on long-term stable antipsychotic treatment (duration of atleast 5 years) entered the study.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride or placebo is administered as “add on” to theantipsychotic treatment, which is kept constant during the whole study.The dose of blinded medication is titrated over a period of 3 weeks in arange from 2.5 to 20 mg b.i.d. Then the medication is maintained underdouble-blind conditions for 2 weeks. After a 2-week wash-out period, thetest drugs are crossed over. Assessments of tardive dyskinesia by meansof the Abnormal Involuntary Movement Scale (AIMS, see obove) and ofParkinsonian extrapyramidal side effects (UPDRS, see above) are madepretreatment and posttreatment. AIMS scores during treatment with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromanehydrochloride are significantly lower than during placebo period.

[0084] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0085] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of extrapyramidal symptoms induced byneuroleptics, in particular of akathisia and/or tardive dyskinesia, inwhich the pharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0086] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0087] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of extrapyramidal symptoms induced byneuroleptics, in particular of akathisia and/or tardive dyskinesia, inwhich the pharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0088] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofextrapyramidal symptoms induced by neuroleptics.

[0089] The present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of tremor.

[0090] Tremor includes all types of tremors such as essential tremor,activated physiological tremor, cerebellar tremor, orthostatic tremor ordrug-induced tremor.

[0091](R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof are particularly useful for thetreatment of essential tremor and/or drug-induced tremor.

[0092] Typical animal models utilize either genetic mutant animals orare models where tremor is induced by a pharmacological agent (forreview: H. Wilms et al., Mov. Disord., 1999; 14: 557-571).

[0093] Typical genetic models in mutant animals are the Campus Syndromein the Pietrain pig according to A. Richter et al. (Exp. Neurology,1995; 134: 205-213) or the Weaver mutant mouse according to J. R. Simonand B. Ghetti (Mol. Neurobiol., 1994; 9: 183-189). In the CampusSyndrome model, these mutant pigs show a high-frequency tremor whenstanding and during locomotion, but not while lying at rest. Assessmentof tremor is made by accelerometric recording. In the Weaver mutantmouse, degenerative cerebellar atrophy is fould in association withtremor, gait instability, and toppling over the sides after a few steps.Gait disability and toppling result in dramatically reduced locomotoractivity measured by the distance travelled and the time spent withambulation in conventional activity cages.

[0094](R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof improve the Campus Syndrome inthe Pietrain pig, i.e. reduce disabling tremor when standing and duringlocomotion, and enhance locomotor activity in the Weaver mutant mouse.

[0095] A typical animal model for drug-induced tremors is theoxotremorine-induced tremor (e.g. H. Hallberg and O. Almgren, ActaPhysiol. Scand., 1987; 129: 407-13; J. G. Clement and W. R. Dyck, J.Pharmacol. Meth., 1989; 22: 25-36). Oxotremorine induces tremor which ismeasured by a rating scale.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof inhibit oxotremorine-inducedtremors.

[0096] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0097] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of tremors, in particular of essentialtremors and/or drug-induced tremors, in which the pharmacologicallyacceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0098] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0099] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of tremors, in particular of essentialtremors and/or drug-induced tremors, in which the pharmacologicallyacceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0100] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment oftremor.

[0101] The present invention relates to the use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders chosenfrom the group consisting of Gilles de la Tourette syndrome, ballism,myoclonus, restless legs syndrome and Wilson's disease.

[0102] A typical animal model for myoclonus is myoclonus induced by anacute hypoxic episode according to D. D. Truong et al., Mov. Dsiord.,1994; 9: 201-206). In this model of posthypoxic myoclonus, rats undergoa cardiac arrest for 8 minutes and are resuscitated thereafter.Myoclonic jerks occur spontaneously but can be provoked by auditorystimulation, too, worsening over the days following cardiac arrest.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof dose-dependently reduce thenumber of spontaneous and auditory-evoked myoclonic jerks.

[0103] A preferred salt of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0104] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of extrapyramidal movement disorderschosen from the group consisting of Gilles de la Tourette syndrome,ballism, myoclonus, restless legs syndrome and Wilson's disease in whichthe pharmacologically acceptable salt is(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0105] A preferred salt of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0106] Therefore the invention relates to the use for the manufacture ofa medicament for the treatment of extrapyramidal movement disorderschosen from the group consisting of Gilles de la Tourette syndrome,ballism, myoclonus, restless legs syndrome and Wilson's disease in whichthe pharmacologically acceptable salt is(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride.

[0107] Additionally, the invention relates to the use of apharmaceutical composition containing at least one compound of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof together with at least onesolid, liquid or semiliquid excipient or adjunct for the treatment ofextrapyramidal movement disorders chosen from the group consisting ofGilles de la Tourette syndrome, ballism, myoclonus, restless legssyndrome and Wilson's disease.

[0108] The extrapyramidal movement disorders such asSteele-Richardson-Olszewski syndrome (=progressive supranuclear palsy),cortico-basal degeneration, olivo-ponto cerebellar atrophy, Shy Dragersyndrome, minor chorea, chorea of pregnancy, writer's cramp,blepharospasm, Meige syndrome, dopa-sensitive dystonia, Gilles de laTourette syndrome, ballism, myoclonus, restless legs syndrome, andWilson's disease are not frequent enough to perform regular double-blindtrials. However, the medical need in this field is pressing since nosufficient therapies are available so far.

[0109] Therefore, open-label observations in few selected patients arean adequate method to demonstrate the efficacy of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof.

[0110] All the pharmaceutical preparations used for the treatment ofextrapyramidal movement disorders and/or for the treatment of adverseeffects of anti-Parkinsonian drugs in extrapyramidal movement disordersincluding the medicinal combination can be used as pharmaceuticals inhuman or veterinary medicine.

[0111] The compositions of the invention are preferably administeredparenterally, or better still orally, although the other routes ofadministration, for instance such as rectal administration, are notexcluded.

[0112] Suitable excipients are organic or inorganic substances which aresuitable for enteral (e.g. oral), parenteral or topical adminstrationand which do not react with(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for example water, vegetableoils, benzyl alcohols, alkylene glycols, polyethylene glycols, glyceroltriacetate, gelatine, carbohydrates such as lactose or starch, magnesiumstearate, talc, petroleum jelly. Forms which are used for oraladministration are, in particular, tablets, pills, sugar-coated tablets,capsules, powders, granules, syrups, liquids or drops, forms for rectaladministration are, in particular suppositories, forms for parenteraladministration are, in particular, solvents, preferably oily or aqueoussolutions, furthermore suspensions, emulsions or implants, and forms fortopical administration are transdermal plasters, ointments, creams orpowders.(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof may also be lyophilized and theresulting lyophilisates used for example for the preparation ofinjectable products. The abovementioned preparations can be insterilized form and/or comprise auxiliaries such as glidants,preservatives, stabilizers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, colourings,flavourings and/or other active ingredients, e.g. one or more vitamins.

[0113] Preparations may, if desired, be designed to give slow release of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof or(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof.

[0114] The examples which follow relate to pharmaceutical products:

EXAMPLE A Vials

[0115] A solution of 100 g of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridyl-methyl-aminomethyl]-chromaneor a physiologically acceptable salt thereof and 5 g of disodiumhydrogen phosphate in 3 l of twice-distilled water is brought to pH 6.5with 2N hydrochloric acid, filter-sterilized, filled into vials,lyophilized under sterile conditions and sealed in sterile form. Eachvial comprises 5 mg of active ingredient.

EXAMPLE B Suppositories

[0116] A mixture of 20 g of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridyl-methyl-aminomethyl]-chromaneor a physiologically acceptable salt thereof is melted with 100 g ofsoya lecithin and 1400 g of cocoa butter, and the mixture is poured intomoulds and left to cool. Each suppository comprises 20 mg of activeingredient.

EXAMPLE C Solution

[0117] A solution is prepared from 1 g of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof, 9.38 g of NaH₂PO₄.2H₂O, 28.48 gof Na₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml oftwice-distilled water. The pH is brought to 6.8, and the solution ismade up to 1 l and sterilized by irradiation. This solution can be usedin the form of eyedrops.

EXAMPLE D Ointment

[0118] 500 mg of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof are mixed with 99.5 g ofpetroleum jelly under aseptic conditions.

EXAMPLE E-1 Tablets

[0119] A mixture of 1 kg of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridyl-methyl-aminomethyl]-chromaneor a physiologically acceptable salt thereof, 4 kg of lactose, 1.2 kg ofpotato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate istableted in the customary manner in such a way that each tabletcomprises 10 mg of active ingredient.

EXAMPLE E-2 Tablets

[0120] A mixture of 20 g of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridyl-methyl-aminomethyl]-chromanehydrochloride, 1 kg of l-dopa, 250 g benserazide, 4 kg of lactose, 1.6kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate istableted in the customary manner in such a way that each tabletcomprises 0.2 mg(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromanehydrochloride, 10 mg of l-dopa and 2.5 mg benserazide.

EXAMPLE F Sugar-Coated Tablets

[0121] A mixture is tableted analogously to EXAMPLE E, and the tabletsare subsequently coated in the customary manner with a coating ofsucrose, potato starch, talc, tragacanth and colouring.

EXAMPLE G Capsules

[0122] 2 kg of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof are filled into hard gelatincapsules in the customary manner so that each capsule comprises 20 mg ofthe active ingredient.

EXAMPLE H Ampoules

[0123] A solution of 1 kg of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridyl-methyl-aminomethyl]-chromaneor a physiologically acceptable salt thereof in 60 l of twice-distilledwater is filter-sterilized, filled into ampoules, lyophilized understerile conditions and sealed in sterile form. Each ampoule comprises 10mg of active ingredient.

EXAMPLE I Spray for Inhalation

[0124] 14 g of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof are dissolved in 10 l ofisotonic NaCl solution, and the solution is filled into commerciallyavailable pump-operated spray containers. The solution can be sprayedinto mouth or nose. One actuation (approximately 0.1 ml) corresponds toa dose of approximately 0.14 mg.

1. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders. 2.Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in idiopathic Parkinson's disease.
 3. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of idiopathic Parkinsons's disease.
 4. Useof (R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromaneor a physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in Parkinson's syndromes.
 5. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of Parkinsons syndromes.
 6. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dyskinetic and choreatic syndromes. 7.Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dystonic syndromes.
 8. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal symptoms induced byneuroleptics
 9. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of tremor.
 10. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders chosenfrom the group consisting of Gilles de la Tourette syndrome, ballism,myoclonus, restless legs syndrome and Wilson's disease. 11.Pharmaceutical composition comprising, as active principles, (i)(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof, and (ii) at least oneanti-Parkinsonian drug, in combination with one or more pharmaceuticallyacceptable excipients.
 12. Composition according to claim 11 forenhancing the anti-Parkinsonian effect of the anti-Parkinsonian drug.13. Composition according to claim 11, in which (i) the active principleis in the form of its hydrochloride and (ii) the conventionalanti-Parkinsonian drug is l-dopa.
 14. Composition according to claim 11,in which (i) the active principle is in the form of its hydrochlorideand (ii) the conventional anti-Parkinsonian drug is l-dopa combined withbenserazide.
 15. Composition according to claim 11, in which (i) theactive principle is in the form of its hydrochloride and (ii) theconventional anti-Parkinsonian drug is l-dopa combined with carbidopa.16. Use of(R/S)-(±)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane ora physiologically acceptable salt thereof in combination with at leastone anti-Parkinsonian drug, for the preparation of a medicinalcombination intended to enhance the anti-Parkinsonian effect of saidanti-Parkinsonian drugs.
 17. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders. 18.Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in idiopathic Parkinson's disease.
 19. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of idiopathic Parkinsons's disease.
 20. Useof (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane ora physiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of adverse effects of anti-Parkinsoniandrugs in Parkinson's syndromes.
 21. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of Parkinsons syndromes.
 22. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dyskinetic and choreatic syndromes. 23.Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of dystonic syndromes.
 24. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal symptoms induced byneuroleptics
 25. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of tremor.
 26. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chromane or aphysiologically acceptable salt thereof, for the manufacture of amedicament for the treatment of extrapyramidal movement disorders chosenfrom the group consisting of Gilles de la Tourette syndrome, ballism,myoclonus, restless legs syndrome and Wilson's disease. 27.Pharmaceutical composition comprising, as active principles, (i)(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof, and (ii) at least oneanti-Parkinsonian drug, in combination with one or more pharmaceuticallyacceptable excipients.
 28. Composition according to claim 27 forenhancing the anti-Parkinsonian effect of the anti-Parkinsonian drug.29. Composition according to claim 27, in which (i) the active principleis in the form of its hydrochloride and (ii) the conventionalanti-Parkinsonian drug is l-dopa.
 30. Composition according to claim 27,in which (i) the active principle is in the form of its hydrochlorideand (ii) the conventional anti-Parkinsonian drug is l-dopa combined withbenserazide.
 31. Composition according to claim 27, in which (i) theactive principle is in the form of its hydrochloride and (ii) theconventional anti-Parkinsonian drug is l-dopa combined with carbidopa.32. Use of(S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethyl-aminomethyl]-chromane or aphysiologically acceptable salt thereof in combination with at least oneanti-Parkinsonian drug, for the preparation of a medicinal combinationintended to enhance the anti-Parkinsonian effect of saidanti-Parkinsonian drugs.